This renewal application of our Program Project consists of 8 projects which explore ionic, electrical and mechanical factors contributing to the pathophysiology of sudden cardiac death. These projects utilize membrane vessicles and lipid bilayers of sarcoplasmic reticulum, guinea pig papillary muscles, in situ and in vivo pig hearts and man. They employ microelectrodes, ion- selective electrodes and programmed electrical stimulation and are supported by an animal/electrode core, a computer/biostatistics core, an electronics core and an administrative core. The projects are united by one or more of 4 common themes: the pathogenesis of sudden cardiac death, the correlation between the ionic, electrical and mechanical changes resulting from ischemia, the effects of drugs on the ischemic process and of ischemia on the effects of the drugs, and the effects of increasing rate on the ischemia induced changes. These projects are divided into 3 groups. The three in group A explore the ionic, electrical and mechanical correlations during low flow and no flow ischemia in the in situ and in vivo pig heart. They use multiple ion-specific electrodes and extensive computer technology. The three projects in group B use membrane vessicles, isolated superfused papillary muscles and microelectrode techniques in order to gain a more fundamental understanding of the ionic, electrical and mechanical alterations induced by ischemia, the factors causing slow conduction and the mechanism of action of cardio-active drugs. The two projects in group C seek a greater understanding of factors predisposing to sudden cardiac death in man. They attempt to identify prospectively those at highest risk for this ultimate event and to prevent its occurrence. The program involves investigators from the Department of Biochemistry, Physiology, Medicine, Biostatistics, and Biomedical Mathematics and Engineering and includes collaborations with Dr. Michiel Janse and his co workers at the University of Amsterdam, Holland and Dr. Bernard Gersch and co workers at the Mayo Clinic/medical School in Rochester, MN. The eight projects in this renewal application are the direct outgrowth of studies conducted in the 5 projects comprising our current Program. They reflect the maturation of our concepts and ideas resulting from the integrated, multidiscipline approach made possible by the Program Project mechanism.